Hiv Integrase Inhibitors

• US 20090312335A1
• Filed: 10/23/2006
• Published: 12/17/2009
• Est. Priority Date: 10/27/2005
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Wai, John S, Lyle, Terry A., Williams, Peter D.
• Application Number:
  US12/084,158
• Publication Number:
  US 20090312335A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Substituted hydroxytetrahydropyrrolopyrazinone and substituted hydroxytetrahydro-pyrazolopyrazinone compounds of Formula (I) are inhibitors of HIV integrase and inhibitors of HIV replication: (I) wherein R¹, R², R³, R⁴; R⁵, X, ring A, and Q are as defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein the compound is of Formula (I-1),

3. The compound of claim 2, wherein R⁴ is H or —

R^j; and

R^j is;

(i) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently —

C_1-4 alkyl, —

C_1-4 alkyl-OH, —

C_1-4 alkyl-O—

C_1-4 alkyl, —

C_1-4 alkyl-O—

C_1-4 haloalkyl, —

C_1-4 alkyl-N(R^aR^b), —

C_1-4 alkyl-C(═

O)N(R^aR^b), —

C_1-4 alkyl-C(═

O)R^a, —

C_1-4 alkyl-CO₂R^c, —

C_1-4 alkyl-S(O)_nR^d, —

O—

C_1-4 alkyl, —

C_1-4 haloalkyl, —

O—

C_1-4 haloalkyl, —

OH, halo, —

N(R^aR^b), —

C(═

O)N(R^aR^b), —

C(═

O)R^a, —

CO₂R^c, —

SH, —

S(O)_nR^d, or —

SO₂N(R^aR^b);

or

(ii) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, and dioxanyl;

wherein the saturated heterocyclic ring is;

(a) optionally substituted with from 1 to 4 substituents each of which is independently halogen, —

C_1-4 alkyl, —

C_1-4 haloalkyl, —

O—

C_1-4 alkyl, —

O—

C_1-4 haloalkyl, or oxo; and

(b) optionally mono-substituted with phenyl or HetA;

wherein HetA is a heteroaromatic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl;

wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently —

C_1-4 alkyl, —

C_1-4 haloalkyl, —

O—

C_1-4 alkyl, —

O—

C_1-4 haloalkyl, or oxo.

4. The compound of claim 3, wherein R^j is phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently —

C_1-4 alkyl, —

C_1-4 alkyl-OH, —

C_1-4 alkyl-O—

C_1-4 alkyl, —

C_1-4 alkyl-O—

C_1-4 haloalkyl, —

C_1-4 alkyl-N(R^aR^b), —

C_1-4 alkyl-C(═

O)N(R^aR^b), —

C_1-4 alkyl-C(═

O)R^a, —

C_1-4 alkyl-CO₂R^d, —

C_1-4 alkyl-S(O)_nR^d, —

O—

C_1-4 alkyl, —

C_1-4 haloalkyl, —

O—

C_1-4 haloalkyl, —

OH, halo, —

N(R^aR^b), —

C(═

O)N(R^aR^b), —

C(═

O)R^a, —

CO₂R^c, —

SH, —

S(O)_nR^d, or —

SO₂N(R^aR^b).

5. The compound of claim 4, wherein ring A is a 5- or 6-membered aromatic monocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S.

6. The compound of claim 5, wherein ring A is oxadiazolyl, triazolyl, thiadazolyl, oxazolyl, tetrazolyl or pyrimidinyl.

7. The compound of claim 6, wherein ring A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,3,4-thiadazolyl, 1,3-oxazol-2-yl, 2-tetrazol-5-yl, 1-tetrazol-5-yl or 4-pyrimidinyl.

8. The compound of claim 5, wherein Q is —

C_1-3 alkylene.

9. The compound of claim 8, wherein Q is —

CH₂—

.

10. The compound of claim 9, wherein R⁵ is phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently selected from fluoro, bromo, chloro, —

OH, —

C_1-4 alkyl, —

C_1-4 fluoroalkyl, —

O—

C_1-4 alkyl, —

O—

C_1-4 fluoroalkyl, —

(CH₂)_1-2—

N(R^aR^b), —

SO₂R^a, —

(CH₂)_0-2—

CO₂R^a, —

(CH₂)_0-2—

N(R^a)CO₂R^b, —

NO₂, —

SR^a, —

N(R^aR^b) and phenyl.

11. The compound of claim 1, wherein the compound is:

12. A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

14. A method for treating infection by HIV or for treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1.

19. A combination which is (i) a compound or a pharmaceutically acceptable salt thereof according to claim 1, and (ii) an HIV infection/AIDS antiviral agent selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors;

wherein the compound of (i) or its pharmaceutically acceptable salt and the HIV infection/AIDS antiviral agent of (ii) are each employed in an amount that renders the combination effective for treating infection by HIV, or for treating or delaying the onset of AIDS.

13. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. (canceled)